Endogenous opioid peptides, including proopiomelanocortin (POMC)-derived beta-endorphin, modulate neurobiological responses to ethanol and administration of ethanol alters the expression of POMC and beta- endorphin. Given that ethanol has direct effects on POMC activity, it is possible that the other POMC-derived peptides, namely the melanocortins (MCs), are also involved with neurobiological responses to ethanol. MC peptides include alpha-melanocyte stimulating hormone (alpha-MSH), which is synthesized in the arcuate nucleus of the hypothalamus, the nucleus of the solitary tract, and the medulla, regions that project to many brain regions of known relevance to alcoholism. Pre-treatment with MC receptor (MCR) agonists reduce heroin self-administration and chronic administration of morphine or cocaine increases MC-4 receptor (MC4R) levels in striatum rats. Interestingly, rats selectively bred for high ethanol consumption have abnormal levels of MC-3 receptor (MC3R) and MC4R in the nucleus accumbens (NAc) and hypothalamus, and we have provided preliminary findings indicating that intracerebroventricular (i.c.v.) infusion of a selective MC4R agonist reduces, while i.c.v. infusion of a non-selective MCR antagonist increases, ethanol drinking by C57BL/6J mice. Hence, the specific aims proposed below will test the guiding hypothesis that MCR signaling modulates ethanol consumption and neurobiological responses to ethanol. Specifically, we will determine if MC3R and/or MC4R signaling limits self-administration of ethanol by mice (Specific Aim 1), if the endogenous MCR antagonist, agouti-related protein (AgRP), promotes ethanol self-administration by mice (Specific Aim 2), if MCR agonists and antagonists influence ethanol consumption by acting on the MC3R and/or MC4R (Specific Aim 3), and if administration of ethanol will increase alpha-MSH and MC3R/MC4R levels while at the same time decrease AgRP levels, a response that could theoretically protect against uncontrolled ethanol drinking (Specific Aim 4).